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Friday, January 13, 2012

Contrary to concerns professed lately by opponents of opioid analgesia, higher than usual doses of these medications could be just the thing to prevent acute pain from becoming a chronic, life-changing malady. As was recently successfully demonstrated in a preclinical study, the concept of early, short-term, high-dose opioid administration to quickly manage pain is a radical departure from usual practice and may offer interesting possibilities for better pain care.

In the study — published recently in the journal Science [Drdla-Schutting et al. 2012], and further reported in the journal Nature [Frood 2012] — researchers at the Department of Neurophysiology, Center for Brain Research, Medical University of Vienna, report discovering new effects of opioids when given at a very high dose rather than continuously at typical lower does.

According to the articles, chronic pain in many cases is a nerve condition lingering long after an acute pain-causing stimulus has receded. One of the researchers, Jürgen Sandkühler, notes that acute stimuli can change how the central nervous system deals with pain. In a model known as long-term potentiation (LTP), nerves carrying pain signals may fire repeatedly, turning on a cellular pain amplifier that influences the development of a chronic pain state. Opioid analgesics at usual doses can be effective, at least short term, but they often have limitations in some patients for providing ongoing relief of chronic pain.

Sandkühler and colleagues decided to push the boundaries of opioid actions to see whether the drugs could impact the underlying LTP problem of chronic pain at an early stage. The team induced LTP in 25 rats by exposing nerve fibers known to carry pain signals to either low- or high-frequency electrical stimulation, and some of the animals were injected with capsaicin, the pain-causing ingredient in chilli peppers, as an alternative noxious stimuli. Essentially, the three types of stimuli induced acute pain and then chronic hyperalgesia in the animals.

After the pain stimulus was discontinued, the researchers gave the animals very high intravenous doses of remifentanil, a potent ultra-short-acting opioid often used as a component of surgical anesthesia. As expected, the acute-pain signaling declined immediately upon opioid administration; however, once the short-term opioid effects wore off, the hyperalgesic chronic pain effects of LTP also were significantly reduced. A second infusion of remifentanil an hour later abolished LTP completely and restored the animals' pain sensitivity to normal. Similar beneficial effects were found in rats treated with all 3 forms of pain-inducing stimulation.

The high-dose opioid not only dampened acute pain but erased memory traces of pain in the central nervous system. However, treating the animals with only half the dose of remifentanil did not produce the same benefits. Sandkühler suggests that a threshold level of the drug is needed to disrupt the movement of calcium signalling ions between nerves and thereby neutralize the LTP.

“The dose of drugs we use is very high, probably 2 to 4 times higher than used for normal pain control,” Sandkühler states in the Nature article. “The animals almost stop breathing, which is probably one reason why this was not discovered before.” But he adds that the equivalent high dose amount of the opioid for a human is well below a fatal dose, and some early experiments have shown that people can tolerate it.

COMMENTARY: Normally, we do not report on preclinical experiments in animals for the obvious reason that whatever is found may have no clinical validity in humans. This also could be the case here; however, this research is rather provocative in that the scientific rationale appears to have some merit, yet the approach contradicts current attitudes and practices regarding opioid therapy.

There has been some discussion in the literature that, by treating acute pain of various types quickly and aggressively, the chances of it becoming a chronic condition might be reduced. However, opioids are often avoided if possible as acute-pain therapy, and the current advice of “start low and go slow” when it comes to opioid dosing might actually favor in certain cases the development of long-term potentiation (LTP) that fosters chronic pain. Perhaps, what is most needed is higher rather than lower opioid dosing at the outset, at least for a brief period of time and, certainly, under safe conditions.

Of course, much more research is needed to assess the opioid agents, doses, patients, and acute pain conditions that are most amenable to this approach; and, its safety. Meanwhile, it is merely something to think about.

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